The present invention is for novel benzothiophene, benzofuran and indole thiazepinones, oxazepinones and diazepinones and pharmaceutically acceptable salts thereof, used to prevent the adhesion of leukocytes to endothelial cells. Leukocyte adherence to vascular endothelium is integral to the pathogenesis of inflammation. The adhesion process precedes transendothelial migration of leukocytes into surrounding tissue and ensuing tissue damage. Compounds that can block this initial adhesive interaction are expected to have efficacy in the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, and psoriasis. Other indications would include but are not limited to adult respiratory distress syndrome, reperfusion injury, ischemia, ulcerative coliris, vasculitides, atherosclerosis, inflammatory bowel disease and tumor metastases.
Adhesion receptors are organized into three main families: the selectins, the immunoglobulin superfamily, and the integrins (Nature, 346:426 (1990)). Members of all three classes are involved in mediating leukocyte adhesion during inflammation (for reviews of this area see: Thrombosis and Hemostasis, 65(3);223 (1991), Clinical and Experimental Allergy, 20:619 (1990), Transplantation, 48:727 (1989), Biochemical Pharm, 40 (8):1683 (1990)). Endothelial leukocyte adhesion molecule-1 (ELAM-1 or E-selectin) is a member of the selectin family of glycoproteins that promote cell-cell adhesion. E-selectin is reported to be maximally expressed on the surface of endothelial cells 4 hours after stimulation of the endothelial cells with cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor .alpha. (TNF-.alpha.) or other inflammatory mediators, such as lipopolysaccharide (LPS) (Pro. Nat. Acad. Sci., 84:9238 (1987).
Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin superfamily. It is also upregulated with maximum expression occurring 12-24 hours after stimulus. It has been shown that 4 hours after the endothelial cells are stimulated with an inflammatory mediator both E-selectin and ICAM-1 are present on the cell surface (J. Clin. Invest., 82: 1746 (1988) and J. Immun., 137:1893 (1986), Blood, 78:2721 (1991)).
The benzothiophene, benzofuran and indole thiazepinones, oxazepinones and diazepinones of the present invention have been shown to inhibit the adhesion of neutrophils to human umbilical vein endothelial cells (HUVECS) stimulated with TNF.alpha. in an in vitro assay.